PROJECT SUMMARY/ABSTRACT In 2017, tuberculosis, caused by Mycobacterium tuberculosis (M.tb), afflicted 10 million people worldwide and resulted in 1.6 million deaths. Approximately a third of the world's population harbors an M.tb infection, but less than 10% develops active disease. The majority establish a controlled latent infection that is difficult to treat when reactivated in the aged and those with weakened immune systems. In addition, the emergence of multi- drug resistant strains is a significant concern. TB eradication will require a multi-pronged approach, including development of more effective vaccines. BCG, the current vaccine, is ineffective in the therapeutic setting. Early stage studies suggest that vaccines that generate both systemic and tissue resident Th1/17 polarized memory will provide long-lived protective immunity. Bordetella Colonization Factor A (BcfA) is a protein adjuvant that elicits Th1/17 responses and strongly attenuates Th2 responses. In this application, we will test the hypothesis that acellular vaccines comprised of purified M.tb antigens adjuvanted with BcfA (BcfA-aV), will elicit Th1/17 skewed antigen-specific systemic and mucosal T cell responses that provide effective long-lived immunity against M.tb infection, and attenuate establishment of latent TB. In Specific Aim 1, we will test whether immune responses generated by BcfA-aV provide protection against M.tb infection. In Specific Aim 2, we will characterize the phenotype of the systemic and mucosal T cell response elicited by the vaccine. IMPACT: This work will test the ability of a novel acellular vaccine formulation to elicit strong immune responses against M. tb antigens that will protect against active TB and reduce establishment of latent TB. The vaccine leverages the strong adjuvant activity of BcfA and an immunization strategy that generates tissue resident and systemic memory. The data generated here will serve as the launching pad for a larger project that will further characterize the vaccine-induced protective immune response and test the therapeutic efficacy of this novel vaccine as a treatment for latent TB.